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Cynomolgus MonkeysおよびMiceにおけるCoproporphyrin I (CPI)の吸収および処分：OATP阻害の可能性を伝えるためのCPIの使用を支持する薬物動態学的証拠
Absorption and Disposition of Coproporphyrin I (CPI) in Cynomolgus Monkeys and Mice: Pharmacokinetic Evidence to Support the Use of CPI to Inform the Potential for OATP Inhibition.
PMID: 32482623 DOI: 10.1124/dmd.120.090670.
抄録
Despite a recent expansion in the recognition of coproporphyrin's (CP's) potential utility as an endogenous biomarker of OATP1B activity, there have been few detailed studies of C's pharmacokinetic behavior and an overall poor understanding of its pharmacokinetic fate from tissues and excretion. Here, we describe the pharmacokinetics of deuterium-labeled coproporphyrin I (CPI-d8) in cynomolgus monkeys following oral and intravenous administration. CPI-d8 has a half-life and bioavailability of 7.6 h and 3.2&, respectively. Cynomolgus monkeys received oral cyclosporin A (CsA) at 4, 20, and 100 mg/kg which yielded maximum blood concentrations () and area under the plasma concentration-time curve () values of 0.19, 2.5, and 3.8 &[muM, and 2.7, 10.5, and 26.6 &[muM●h, respectively. The apparent CsA-dose dependent increase in the ratio () of CPI-d8 (1.8, 6.2, and 10.5), CPI (1.1, 1.4, and 4.4), and CPIII (1.1, 1.8, and 4.6) at 4, 20, and 100 mg, respectively. In contrast, the plasma concentrations of CPI and CPIII were generally not affected by IV administration of the renal organic anion and cation transporter inhibitors [probenecid (PROB) and pyrimethamine (PYR), respectively]. In addition, tritium-labeled coproporphyrin I ([H]CPI) showed specific and rapid distribution to the liver, intestine, and kidney after an IV dose in mice using quantitative whole-body autoradiography (QWBA). Rifampin (RIF) markedly reduced the liver and intestinal uptake of ([H]CPI) while increasing the kidney uptake. Taken together, these results suggest that hepatic OATP considerably affects the disposition of CPI in animal models, indicating CPI is a sensitive and selective endogenous biomarker of OATP inhibition. SIGNIFICANCE STATEMENT: This study demonstrated that CPI has favorable oral absorption, distribution, and elimination profiles in monkeys and mice as an endogenous biomarker. It also demonstrated its sensitivity and selectivity as a probe of OATP1B activity. The study reports, for the first time, in vivo pharmacokinetics, tissue distribution, sensitivity, and selectivity of CPI as an OATP1B endogenous biomarker in animals. The data provides preclinical support for exploration of its utility as a sensitive and selective circulating OATP biomarker in humans.
The American Society for Pharmacology and Experimental Therapeutics.